An increase in the intracellular calcium (Cai++) level has been implicated in a variety of cerebral pathologies, from acute ischemia of cardiac arrest or stroke to the chronic effects of neuronal damage and cell death as seen in senile dementias of the Alzheimer type or in aging. However, it is not known, in a dynamic situation in vivo, what may be the source of this Cai: plasma, cerebral extracellular space or intracellular depots, and secondly, what specific biochemical pathways may be involved: influx via the slow L-channels, NMDA receptor related flux, due to free radicals or to decreased energy reserve in hypoxia. Attempts to overcome neurological deficits by using Ca antagonists for the L-channel are not without conflicting results. We propose to determine the Ca fluxes in vivo at different sites of the brain in an animal model. Parallel studies will be made of the fluxes of plasma markers 3H-sucrose and 125I-albumin across the blood brain barrier (BBB), of the formation of cerebral edema and of energy metabolism. Studies will be performed in an animal model with focal cerebral ischemia. Neurological effects will be monitored. The effects of specific inhibitors of the different pathways of Ca flux will be used not only in delineating the biochemical mechanism(s) involved but also in designing approaches to eventual therapy and/or management. Computer simulation of the results will show the temporal and spatial evolution of the effects of ischemia on BBB, the flux of Cai and the cerebral energy metabolism. Acute effects of ischemia important in situations such as traumatic brain injury or stroke will thus be addressed. Regional effects such a sin hippocampus may have implication in the development of dementia. to determine if such pathways are of import in aging of the brain, similar experiments will be performed in old animals including a group made susceptible to ischemic injury by the administration of vasoactive agents.